Increasing evidence indicates that cancer can start before birth. In utero exposure to hormonal disruptor diethylstilbestrol (DES) has been associated with increased breast cancer risk in later life by unknown mechanisms. BPA is a common environmental chemical with estrogenic properties. Perinatal exposure to BPA associated breast cancer risk is emerging as a serious health concern. Previous studies using carcinogen models indicate that perinatal exposure to BPA induces proestrogenic effect in early adult stage and promotes mammary tumor development in these animals, but detailed mechanisms of these effects remain unclear. We have been studying hormonal modulation of erbB-2 mediated breast cancer risk using the MMTV-erbB-2 transgenic model. We demonstrated that in utero exposure to hormonal disruptor genistein or BPA promoted mammary tumor development in later life, which was preceded with significantly altered histoarchitectures and signaling in both estrogen receptor (ER) and erbB-2 pathways in the adult glands. Our data also suggest that in utero exposure to hormonal disruptors may induce the repopulation of mammary stem/progenitor cells. To investigate the molecular mechanisms of in utero exposure to BPA associated mammary tumor risk, we hypothesize that in utero exposure to BPA increase mammary cancer risk of erbB-2 transgenic mice through the induction of ER-erbB-2 crosstalk and the reprogramming of mammary stem cells. The specific aims are: 1) To investigate in utero exposure to BPA induced activation of erbB-2 pathway and the crosstalk between ER and erbB-2 pathways. Modification of ER-DNA binding patterns will be analyzed using functional genomics. 2). To determine the effect of in utero exposure to BPA on the reprogramming of mammary stem/progenitor cells by flow cytometry analysis of stem cell markers and mammary gland transplantation. With this clinically relevant mouse model and novel approaches, the results from this project are expected to have significant impact on breast cancer prevention and management.